The long term objective of this research is to develop a photoreceptor replacement therapy based on delivery of retinal progenitor cells to the subretinal space of the eye to restore vision in patients with retinal degeneration. Limitations of the current polymeric scaffolds used for delivery of retinal progenitor cells are that they induce a foreign body response, have poor mechanical properties, and cannot be easily modified. Addressing these issues will remove a critical barrier to replacement of photoreceptor cells in retinal degenerate patients. The goal of this proposal is to develop and test a new class of degradable polymeric scaffolds for delivery of retinal progenitor cells (RPCs). The following specific aims are proposed: Specific Aim 1: Synthesize a library of degradable elastomeric polymers and evaluate their biocompatibility with RPCs. A new elastomeric degradable polymer known as poly(glycerol-sebacate) was recently reported with mechanical properties similar to those of tissue and ideal for a retinal graft scaffold. Poly(glycerol- sebacate) and a library of structural analogs will be adapted for use with RPCs. Specific Aim 2: Evaluate the ability of the polymers to differentiate RPCs, determine the effect of growth factors on proliferation and differentiation of RPCs, and refine the mechanical properties of a subset of the polymers. A design criterion for the scaffold is that it should be able to induce differentiation of the RPCs to photoreceptors. This property should result from interaction between the polymer and cell, growth factor and cell, or combined polymer, growth factor, and cell. The mechanical properties of a subset of the polymer library that meets these conditions will be optimized for subretinal implantation. Specific Aim 3: Assess the ability of polymer-RPC composite grafts to differentiate toward functional photoreceptors in vivo. A set of optimal polymers and conditions from the preceding specific aims will be used to deliver RPCs to the subretinal space in rhodopsin knockout mice. This mouse strain serves as a model for retinitis pigmentosa. The ability of RPCs to differentiate toward functional photoreceptors in vivo will be assayed. Relevance to public health: The number of Americans afflicted by diseases that cause blindness is increasing dramatically due to the aging population, and currently no treatment exists to restore vision for most of these people. This research seeks to address this problem by eliminating a major obstacle to the development of a vision-restoring therapy. [unreadable] [unreadable] [unreadable]